Aroyl aminoacyl pyrroles for use in the treatment of neuropathic pain

ABSTRACT

Aroyl aminoacyl pyrroles are pharmaceutically useful in treating neuropathic pain, which includes utility for the treatment of neuropathic pain.

This application claims the benefit of Provisional Application Ser. No.60/120,477, filed Feb. 18, 1999.

FIELD OF THE INVENTION

This invention relates to compounds useful in the treatment ofneuropathic pain. More particularly, this invention relates to aroylaminoacyl pyrroles that are useful in the treatment of neuropathic pain.

BACKGROUND OF THE INVENTION

The conditions grouped under the term neuropathic pain constitute anarea of continuing medical need.

Neuropathic pain is defined as pain caused by aberrant somatosensoryprocessing in the peripheral or central nervous system. Chronic ordebilitating conditions, such as post-herpetic neuralgia and phantomlimb syndrome, are categorized as neuropathic pain. Such conditions arewidespread and cause unnecessary pain and suffering. Moreover, currentmethods of treating neuropathic pain are often inadequate and result inhuge medical costs.

Anticonvulsants have been widely suggested for the treatment ofneuropathic pain, Nadin Attal, et al., Effects of Gabapentin on theDifferent Components of Peripheral and Central Neuropathic PainSyndromes: A Pilot Study, Fr. Eur. Neurol. 1998, 40(4), 191-200. Suchcompounds are believed to act preferentially on lancinating, shootingpain. Gabapentin induced a moderate and statistically significant reliefof ongoing spontaneous pain, was particularly effective in reducingparoxysmal pain and was significantly effective on brush-induced andcold allodynia (a painful response to normally innocuous stimuli). Incontrast, no effect on detection and pain thresholds to staticmechanical and hot stimuli was observed. The study suggests thatgabapentin is preferentially antihyperalgesic (mediates exaggeratedresponses to normally painful stimuli) and/or antiallodynic andsimilarly effective in pain due to peripheral nerve injuries or centrallesions.

Other anticonvulsants have been useful in treating neuropathic pain,Richard P. Shank, et al., Anticonvulsant Derivatives Useful in TreatingNeuropathic Pain, U.S. Pat. No. 5,760,007. As disclosed in thisreference, studies conducted to evaluate the efficacy of theanticonvulsant topiramate in an animal model of neuropathic pain gaveevidence of pharmacological activity in treating neuropathic pain.

Also, therapeutic compositions of anticonvulsants and non-toxic NMDA(N-methyl-D-aspartate) antagonists in neuropathic pain-alleviatingamounts have been shown to block a major intracellular consequence ofNMDA receptor activation, Frank S. Caruso, et al., PharmaceuticalCompositions Containing Anticonvulsants and NMDA Receptor Antagonistsfor Treating Neuropathic Pain, WIPO Patent No. 98/07447. This referenceteaches the use of these anticonvulsants as suitable for use in thiscombination: lamotrigine, gabapentin, valproic acid, topiramate,famotidine, phenobarbital, diphenylhydantoin, phenytoin, mephenytoin,ethotoin, mephobarbital, primidone, carbamazepine, ethosuximide,methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide,acetazolamide, progabide, clonazepam, divalproex sodium, magnesiumsulfate injection, metharbital, paramethadione, phenytoin sodium,valproate sodium, clobazam, sulthiame, dilantin, diphenylan andL-5-hydroxytryptophan.

The aroyl amino acyl pyrrole compounds of the present invention havebeen previously disclosed and taught as useful anticonvulsants, RichardJ. Carmosin, John R. Carson, Philip M. Pitis, Anticonvulsant Aroyl AminoAcyl Pyrroles, U.S. Pat. No. 5,332,736. The compounds of the presentinvention, however, have not previously been shown as effective for thetreatment of neuropathic pain. It is an object of the present inventionto teach a method for the treatment of neuropathic pain using thecompounds of the present invention.

SUMMARY OF THE INVENTION

Briefly, there is provided by the present invention a method for thetreatment of neuropathic pain comprising the step of administering to amammal suffering from such condition an effective amount, in apharmaceutically acceptable carrier, of an active compound of theformula:

wherein,

A is simultaneously both

 n is an integer from 1 to 5;

R¹ is selected from the group consisting of H and C₁₋₄alkyl;

R² and R³ are selected from the group consisting of H and C₁₋₄alkyl;

R⁴ and R⁵ are independently selected from the group consisting of H,C₁₋₄alkyl, phenyl C₁₋₄ alkyl and substituted phenyl C₁₋₄ alkyl where thesubstituent is on phenyl and selected from the group consisting ofmethyl and methoxy, or in the alternative, are fused and together withsaid nitrogen form a heterocyclic ring selected from the groupconsisting of 4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl,1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-2-yl,

 wherein Y is S or O, x is 3 to 7 and R⁷ is selected from the groupconsisting of methyl and hydroxymethyl; and

R⁶ is selected from the group consisting of halo, C₁₋₄ alkyl, C₁₋₄alkoxy, hydroxy, nitro, amino, C₁₋₄ acylamino, cyano, trihalo C₁₋₄alkyl,C₁₋₄alkylsulfonyl, C₁₋₄alkylsulfinyl, and C₁₋₄ acyl,

including pharmaceutically acceptable acid addition salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention used in the treatment ofneuropathic pain may be placed into two categories, those having benzoylat the 2-position and those having benzoyl at the 4-position. Bothcategories of compounds may be prepared by variations of what isfundamentally the same reaction scheme.

Scheme 1 exemplifies the preparation of compounds having benzoyl at the2-position. Referring to Scheme 1, in the first step a simple pyrrole A1is acylated with an appropriately substituted benzoyl chloride B1 toproduce benzoyl pyrrole C1. This acylation may be carried out by simplyheating the benzoyl chloride and the pyrrole in an aprotic solventfollowed by removing excess benzoyl chloride by reaction with a dibasicamine and extraction with HCl. Typical of the aprotic solvents which maybe utilized are aromatic hydrocarbons, such as, benzene, toluene,xylene, chlorobenzene, nitrobenzene, etc.; paraffins, such as, methylcyclohexane, octane, etc.; halocarbons, such as, methyl chloride,chloroform, tetrachloroethane, etc.; ethers, such as, diethyl ether,diglyme, etc.; ketones, such as, methyl ethyl ketone, cyclohexanone,etc.; esters, such as, ethyl butyrate, etc.; nitroalkanes, such as,nitropropane, etc.; or carbon disulfide. The temperature of theacylation will vary depending upon the desired rate of reaction and thesubstituents of pyrrole A1. Preferably the acylation is carried out at atemperature of from about 50 to 250° C. A suitable dibasic amine isdimethyl-3-aminopropyl amine. In the case where R¹ is hydrogen theacylation, as described, may not produce desirable yields. In this case,a Vilsmeier type acylation as employed by J. White and G. McGillivrey,J. Org. Chem., Vol. 42, pp 42-48, 1977 might be expeditiously employed.Subsequently, benzoyl pyrrole C1 is acylated at the 4-position in aFriedel-Crafts reaction with acid chloride D1 to produce2-benzoyl4-alkanoyl pyrrole E1. The Friedel-Crafts reaction is carriedout by refluxing the carboxylic acid chloride D1, in which X is Cl, Bror I, with product C1 in a solvent with a Friedel-Crafts reagentfollowed by treatment with HCl and evaporation of the solvent. SuitableFriedel-Crafts reagents include aluminum chloride, zinc chloride, BF₃ orTiCl₄. Suitable solvents include methylene chloride, 1,2-dichloroethane,carbon tetrachloride or chloroform. The temperature of reflux might varybetween about 30 and 150° C. In the case where R⁶ is amine, it will notsurvive the Friedel-Crafts reaction in good yield. Thus, it should beprotected with well known protecting groups or present as a suitableprecursor substituent, such as, nitro which can thereafter be convertedto amine. In the third reaction, 2-benzoyl-4-alkanoyl pyrrole E1 isaminated with amine F1 to produce the desired 2-benzoyl-4-aminoalkanoylpyrrole G1. The amination may be carried out by heating the reactants E1and F1 neat or in a solvent to a temperature of from about 40 to 120° C.and preferably from about 50 to 90° C. Suitable solvents, whereemployed, include ethanol, i-propanol or toluene.

Scheme 2 exemplifies the preparation of compounds having benzoyl at the4-position. Except for the specifics of the reactants, each step ofScheme 2 is analogous to the corresponding step of Scheme 1 with thereactions and description thereof being identical. Referring to Scheme2, in the first step a simple pyrrole A2 is acylated with anappropriately substituted alkanoyl chloride B2 to produce alkanoylpyrrole C2. Subsequently, alkanoyl pyrrole C2 is acylated at the4-position in a Friedel-Crafts reaction with benzoic acid chloride D2 toproduce 2-alkanoyl-4-benzoyl pyrrole E2. In the third reaction,2-alkanoyl-4-benzoyl pyrrole E2 is aminated with amine F2 to produce thedesired 2-aminoalkanoyl-4-benzoyl pyrrole G2.

Preferred R¹ include hydrogen, methyl, ethyl, n-propyl and i-propyl. Inthe most preferred compounds, R¹ is methyl.

Preferred R² and R³ include hydrogen, methyl, ethyl, n-propyl andi-propyl. In the most preferred compounds, R² and R³ are hydrogen andmethyl.

Preferred R⁴ and R⁵, where independently selected, include hydrogen,methyl, ethyl, n-propyl, i-propyl, benzyl and 2-phenyleth-1-yl where thephenyl ring may be mono- or di-substituted with a substituent selectedfrom the group of methyl and methoxy. In the most preferred compounds,R⁴ and R⁵, where independently selected, are hydrogen, methyl and in atmost one instance benzyl.

Preferred R⁴ and R⁵, where fused and depicted together with nitrogen,include 4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl,1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-2-yl,

In the most preferred compounds, R⁴ and R⁵, where fused and depictedtogether with nitrogen, are piperidine-1-yl, pyrrolidin-1-yl,morpholin-1-yl and imidazol-1-yl.

Preferred R⁶ include bromine, chlorine, methyl, ethyl, methoxy, ethoxy,hydroxy, nitro, amino, formylamino, acetylamino, cyano, perfluoromethyl,3,3,3-trifluoropropyl, methylsulfonyl, methylsulfinyl, formyl, andacetyl. In the most preferred compounds, R⁶ is non-existent, methyl orchloro.

The compounds herein readily form pharmaceutically acceptable acidaddition salts. Such salts include hydrochlorides, sulfates, phosphates,methane sulfonates, fumarates, maleates, citrates, lactates, and thelike. Those skilled in the art will readily recognize suitable methodsfor manufacture and use of the acid addition salts.

The compounds of the present invention are useful in the treatment ofneuropathic pain. The use of the compounds in treating neuropathic painwas determined using an animal model. This model was developed and firstdescribed by S. H. Chung and J. M. Chung, An Experimental Model forPeripheral Neuropathy Produced by Segmental Spinal Nerve Ligation in theRat, Pain, 1992, 50, 355-363 (referred to hereinafter as the “ChungModel”).

Male Sprague-Dawley rats, weighing approximately 200 g each wereanesthetized with isoflurane. The spinal nerve at the level of L₅ wasexposed through an incision just left of the dorsal midline and tightlyligated with 6-0 silk. At various times after surgery, animals weretested for mechanical allodynia with von Frey hairs (monofilaments whichare calibrated to bend under a certain amount of pressure, ranging from0.41 to 15.1 g). In order to calculate a paw withdrawal threshold (PWT),tactile allodynia was measured by recording the pressure at which theaffected paw was withdrawn from graded stimuli according to theprocedure of S. R. Chaplan, J. W. Pogrel, T. L. Yaksh, Role ofVoltage-Dependent Calcium Channel Subtypes in Experimental TactileAllodynia, J. Pharmacol. Exp. Ther. 1994, 269, 1117-1123. Normal ratscan withstand at least 15 g of pressure without responding. Operatedrats, however, can respond to as little as 0.25 g of pressure. Thesurgery was deemed successful if the animal responded with a PWT of lessthan 4 g of pressure applied to the affected paw.

The sham operation consisted of a similar surgery; the spinal nerve wasvisualized without being ligated. These animals were also tested formechanical allodynia and showed no response to greater than 15 g offorce applied to the ipsilateral paw. The results of the assay wereexpressed as percent of the maximum possible effect (% MPE), calculatedas the PWT at the time of testing minus the baseline PWT divided by themaximum PWT (15 g) minus the baseline PWT times 100.

The compounds of the present invention indicated in Table 1 were testedfor activity against neuropathic pain by being dissolved or suspended ineither water or hydroxypropyl methylcellulose, respectively.Postoperative animals between 14 to 42 days were fasted overnight priorto dosing. Animals were orally dosed and dosage volumes were calculatedon a 4 mL/kg basis. The screening dose employed was 30 mg/kg.

The compounds of the present invention listed in Table 1 includecompounds of the formula:

TABLE 1

wherein Ar, R¹, R², R³, R⁴ and R⁵ are selected concurrently from thegroup consisting of: Cpd % # Ar R¹ R² R³ R⁴, R⁵ MPE 9-3 4-ClPh CH₃ CH₃CH₃ —(CH₂)₅— 58 9-4 4-ClPh CH₃ H H C₂H₅, C₂H₅ 61 9-32 4-ClPh CH₃ CH₃ CH₃C₂H₅, C₂H₅ 20 9-39 2,4-diClPh CH₃ CH₃ CH₃ —(CH₂)₄— 19 9-40 4-ClPh CH₃CH₃ CH₃ H, C₂H₅  30* 9-41 2-ClPh CH₃ H H 4-[bis(4- 65fluorophenyl)methylene]- piperidin-1-yl 9-42 4-OMePh CH₃ H H1,2,3,4-tetrahydro-6,7- 53 dimethoxy-isoquinolin- 2-yl *Administered ata dose of 300 mg/kg

The results of the “Chung Model” study are statistically significant andsuggest that the compounds of the present invention are effective inreducing neuropathic pain. For treating neuropathic pain, the compoundsof the present invention may be employed at a daily dosage in the rangeof about 30 to 2000 mg, usually in 2 to 4 divided doses, for an averageadult human. A unit dose would contain about 10 to 500 mg of the activeingredient. More generally, for mammals, the treatment would comprisethe daily administration of from about 0.5 mg/kg to about 50 mg/kg.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention are intimately admixed with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending on the form of preparation desired for administration, e.g.,oral, by suppository, or parenteral. In preparing the compositions inoral dosage form, any of the usual pharmaceutical media may be employed.Thus, for liquid oral preparations, such as, for example, suspensions,elixirs and solutions, suitable carriers and additives include water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents and the like; for solid oral preparations such as, for example,powders, capsules and tablets, suitable carriers and additives includestarches, sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. Suppositories may be prepared, in whichcase cocoa butter could be used as the carrier. For parenterals, thecarrier will usually comprise sterile water, though other ingredients,for example, for purposes such as aiding solubility or for preservation,may be included. Injectable suspensions may also be prepared, in whichcase appropriate liquid carriers, suspending agents and the like may beemployed.

The pharmaceutical compositions herein will contain, per dosage unit,e.g., tablet, capsule, powder, injection, teaspoonful, suppository andthe like, from about 10 to about 500 mg of the active ingredient.

The following examples are offered by way of illustration and not by wayof limitation.

EXAMPLE 1

(4-Methoxyphenyl)(1-methyl-1H-pyrrol-2-yl)-methanone

A solution of 5 g (0.06 mole) N-methylpyrrole and 13.3 g (0.078 mole) of4-methoxybenzoyl chloride in 50 mL of dry toluene was heated underreflux overnight with an argon stream bubbling through the reactionmixture. After cooling, 40 mL of 20% 3-dimethylaminopropylamine in H₂Owas added and the mixture stirred for 45 minutes. Diethyl ether wasadded and the organic solution was washed with 1N HCl, NaHCO₃, water,brine and dried (MgSO₄). The solvent was evaporated in vacuo and theresidue recrystallized from ethanol to give 3.68 g of product: mp.66-68° C.; mass spectrum (CH₄-Cl) m/z=216 (M+1); NMR (CDCl₃) d 7.85 (d,2H); 6.9-7.1 (d,s, 3H); 6.7 (d, 1H); 6.15 (d, 1H); 4.1 (s, 3H); 3.9 (s,3H). Anal Calcd for C₁₃H₁₃NO₂: C, 72.54; H, 6.09; N, 6.51. Found: C,72.59; H, 6.06; N. 6.43.

EXAMPLE 2

By the procedure of Example 1, employing the appropriate aroyl chloridein place of 4-methoxybenzoylchloride, the following products wereproduced:

(2-chlorophenyl)(1-methyl-1H-pyrrol-2-yl)methanone: mp 55-57° C.

(1-methyl-1H-pyrrol-2-yl)(4-nitrophenyl)-methanone: mp 148-150° C.

(3-chlorophenyl)(1-methyl-1H-pyrrol-2-yl)-methanone: bp 115-116° C.(0.004 Torr).

EXAMPLE 3

Ethyl 5-(2,4-dichlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate

A solution of 50 g (0.276 mole) of ethyl1,4-dimethyl-1H-pyrrole-2-acetate and 64 g (0.303 mole) of2,4-dichlorobenzoyl chloride in 310 mL of xylene was heated under refluxfor 4 h under argon. After cooling, a 20% solution of3-dimethylaminopropylamine in H₂O was added and stirred one hour. Theorganic layer was washed twice with 1N HCl, water, brine, and dried(MgSO₄). Evaporation of the solvent in vacuo gave a solid which wasrecrystallized from methanol to give 79.39 g of product: mp 90-92° C.;mass spectrum (Cl—CH₄) m/z=354 (M+1); NMR 300 MHz (CDCl₃) d 7.5 (s, 1H);7.3 (dd, 2H); 6.0 (s, 1H); 4.2 (q, 2H); 3.9 (s, 3H); 3.65 (s, 2H); 1.6(s, 3H); 1.25 (t, 3H). Anal Calcd for C₁₇H₁₇Cl₂NO₃: C, 57.64; H, 4.84;N, 3.95. Found: C, 57.52; H, 4.60; N, 3.80.

EXAMPLE 4

5-(2,4-Dichlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetic Acid

A solution of 2.38 mL (1.1 eq) of 1N NaOH was added dropwise to arefluxing solution of 76.89 g (0.217 mole) of ethyl5-(2,4-dichlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate (3) in 750 mLabsolute ethanol. The mixture was heated under reflux for 20 minutes.The reaction was poured into 3N HCl/ice and extracted three times withdiethyl ether. The organics were washed with water (twice), brine, anddried (MgSO₄). Evaporation of the solvent in vacuo gave a tan oil whichwas crystallized from acetonitrile to give 63.05 g of product: mp140-143° C.; mass spectrum (Cl—CH₄) m/z=326 (M+1); NMR 300 MHz(Me₂SO-d₆) d 7.8 (s, 1H); 7.6 (m, 1H); 7.4 (m, 1H); 6.0 (s, 1H); 3.8 (s,3H); 3.75 (s, 2H); 1.45 (s, 3H). Anal Calcd for C₁₅H₁₃Cl₂NO₃: C, 55.24;H, 4.02; N, 4.29. Found: C, 55.47; H, 3.84; N, 4.29.

EXAMPLE 5

(2,4-Dichlorophenyl)(1,3,5-trimethyl-1H-pyrrol-2-yl)-methanone

A solution of 62.69 g (0.18 mole)5-(2,4-dichlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetic acid (4) in 550mL of propionic acid was heated under reflux overnight then poured intowater. The solution was extracted three times with diethyl ether. Theether solution was washed successively with NaHCO₃, water and brine, anddried (MgSO₄). Evaporation of the solvent in vacuo gave a tan solidwhich was recrystallized from methylcyclohexane: mp 96-98° C.; massspectrum (Cl—CH₄) m/z=282 (M+1); NMR 300 MHz (CDCl₃) d 7.5 (s, 1H);7.35-7.2 (m, 2H); 5.8 (s, 1H); 3.9 (s, 3H); 2.25 (s, 3H); 1.6 (s, 3H).Anal Calcd for C₁₄H₁₃Cl₂NO: C, 59.59; H, 4.64; N, 4.96. Found: C, 59.79;H, 4.39; N, 4.92.

EXAMPLE 6

2-Chloro-1-[5-(2,4-Dichlorobenzoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl]-ethanone

A solution of 48.65 g (0.17 mole) of(2,4-dichlorophenyl)(1,3,5-trimethyl-1H-pyrrol-2-yl)-methanone (5) in480 mL 1,2-dichloroethane was cooled in an ice bath and 53.5 g (0.425mole) of AlCl₃ was added in four portions. A 33.5 mL portion of (0.425mole) chloroacetyl chloride was added dropwise. The ice bath was removedand the reaction allowed to stir for 3 h under argon. A 10 g sample ofAlCl₃ was added and the reaction was stirred overnight. The mixture waspoured into 1N HCl/ice and the organic layer was separated. The aqueouslayer was extracted twice with methylene chloride. The organics werecombined and washed with water, NaHCO₃, water, brine, and dried (MgSO₄).The solvent was evaporated in vacuo and the residue recrystallized frommethylcyclohexane to give 53.50 g of product: mp 100-102° C.; massspectrum (Cl—CH₄) m/z=358 (M+1); NMR 300 MHz (CDCl₃) d 7.55 (s, 1H); 7.4(s, 2H); 4.4 (s, 2H); 3.7 (s, 3H); 2.5 (s, 3H); 1.9 (s, 3H). Anal Calcdfor C₁₆H₁₄NO₂: C, 53.58; H, 3.93; N, 3.91. Found: C, 53.48; H, 3.81; N,3.93.

EXAMPLE 7

1-[5-(2,4-Dichlorobenzoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl]-2-(1-piperidinyl)-ethanone

A solution of 8.0 g (0.022 mole) of2-chloro-1-[5-(2,4-dichlorobenzoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl]-ethanone(6) and 4.64 mL (0.066 mole) of piperidine in 130 mL of 2-propanol washeated under reflux for 1.5 h. The reaction was cooled and the solventevaporated in vacuo. The residue was partitioned between diethyl etherand water and the organic solution was extracted twice with 1N HCl. Asolid was removed by filtration and the filtrate was made basic withsodium bicarbonate. The mixture was extracted with diethyl ether and theether solution was washed with water, brine and dried (MgSO₄). Thesolvent was evaporated in vacuo. The product was converted to thehydrochloride salt and recrystallized from 2-propanol to give 5.97 g ofproduct: mp 177-179° C.; mass spectrum (Cl—CH₄) m/z=393 (m+1); NMR 300MHz (Me₂SO-d₆) d 7.85 (s,1H); 7.6-7.5 (m, 2H); 4.7 (s, 2H); 3.8 (s, 3H);3.6-3.4 (m, 2H); 3.2-3.0 (m, 2H); 2.6 (s, 3H); 2.0 (br s, 4H); 1.8 (s3H). Anal Calcd for C₂₀H₂₂Cl₂N₂O₂: C, 55.22; H, 5.87; N, 6.05. Found: C,55.06; H, 5.89; N, 6.05.

EXAMPLE 8

Using the procedure of Example 6 and employing the appropriate arylpyrrolyl methanone in place of(2,4-dichlorphenyl)(1,3,5-trimethyl-1H-pyrrol-2-yl)-methanone and theapproriate y-chloroacyl choride in place of chloroacetyl chloride, therewere obtained the following products (8-1 through 8-9) having theformula:

wherein Ar, R¹, R², R³ and n are selected concurrently from the groupconsisting of:

No. Ar R¹ R² R³ n 8-1 p-ClPh CH₃ H H 1 8-2 p-ClPh CH₃ CH₃ CH₃ 1 8-3o-ClPh CH₃ H H 1 8-4 p-CH₃OPh CH₃ H H 1 8-5 p-NO₂Ph CH₃ H H 1 8-6 m-ClPhCH₃ H H 1 8-7 p-ClPh H H H 1 8-8 p-ClPh CH₃ H H 3 8-9 p-Cl CH₃ CH₃ CH₃ 4

They are described as follows:

M.P. Yield No. (° C.) (%) Formula Calc'd/ Found 8-1 163 68.1C₁₄H₁₁Cl₂NO₂ C, 56.78; H, 3.74; N, 4.73 C, 56.63; H, 3.82; N, 4.63 8-2141-143 31 C₁₆H₁₅Cl₂NO₂ C, 59.28; H, 4.66; N, 4.32 C, 59.32; H, 4.73; N,4.33 8-3 121-124 91 C₁₄H₁₁Cl₂NO₂ C, 56.78; H, 3.74; N, 4.73 C, 56.72; H,3.66; N, 4.70 8-4 157-159 90 C₁₅H₁₄ClNO₂ C, 61.76; H, 4.84; N, 4.80 C,61.51; H, 4.70; N, 4.69 8-5 173-176 60 C₁₄H₁₁ClN₂O₄ C, 54.83; H, 3.61;N, 9.1 C, 55.11; H, 3.70; N, 9.10 8-6 116-119 67 C₁₄H₁₁Cl₂NO₂ C, 56.78;H, 3.74; N, 4.73 C, 56.87; H, 3.83; N, 4.77 8-7 196-197 91 C₁₃H₉Cl₂NO₂C, 55.35; H, 3.22; N, 4.96 C, 55.76; H, 2.84; N, 4.86 8-8  95-97 39C₁₆H₁₅Cl₂NO₂ C, 59.28; H, 4.66; N, 4.32 C, 59.44; H, 4.24; N, 4.24 8-9 60-65 79 C₁₉H₂₁Cl₂NO₂ C, 62.30; H, 5.78; N, 3.82 C, 62.35; H, 5.74; N,3.75

EXAMPLE 9

Using the procedure of Example 7 and employing the appropriate1-(5-aroylpyrrol-3-yl)-y-chloroalkanone in place of2-chloro-1-[5-(2,4-dichlorobenzoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl]-ethanoneand the appropriate amine in place of piperidine, there were obtainedthe following products (9-1 through 9-42) having the formula:

wherein n, R¹, R², R³, R⁴, R⁵ and Ar are selected concurrently from thegroup consisting of:

No n R¹ R²/R³ R⁴/R⁵ Ar 9-1 1 CH₃ H/H

p-ClPh 9-2 1 CH₃ CH₃/CH₃

p-ClPh 9-3 1 CH₃ CH₃/CH₃

p-ClPh 9-4 1 CH₃ H/H CH₂CH₃/CH₂CH₃ p-ClPh 9-5 1 CH₃ CH₃/CH₃

p-ClPh 9-6 1 CH₃ CH₃/CH₃

p-ClPh 9-7 1 CH₃ CH₃/CH₃

p-ClPh 9-8 1 CH₃ H/H

p-ClPh 9-9 1 CH₃ CH₃/CH₃

p-ClPh 9-10 1 CH₃ H/H

o-ClPh 9-11 1 CH₃ H/H

p-ClPh 9-12 1 CH₃ H/H

o-ClPh 9-13 1 CH₃ H/H

p-ClPh 9-14 1 CH₃ H/H 1-Adamantyl o-ClPh 9-15 1 CH₃ H/H

p-ClPh 9-16 1 CH₃ H/H

p-ClPh 9-17 1 CH₃ H/H

p-OCH₃Ph 9-18 1 CH₃ H/H

p-OCH₃Ph 9-19 1 CH₃ H/H

o-ClPh 9-20 1 CH₃ H/H

p-NO₂Ph 9-21 1 CH₃ H/H

p-NO₂Ph 9-22 1 CH₃ H/H

p-ClPh 9-23 1 CH₃ H/H

m-ClPh 9-24 1 CH₃ H/H

m-ClPh 9-25 1 CH₃ H/H

m-ClPh 9-26 1 H H/H

p-ClPh 9-27 1 H H/H

p-ClPh 9-28 1 CH₃ H/H H/CH₂CH₃ p-ClPh 9-29 1 CH₃ H/H CH₂CH₃/CH₂CH₃p-OCH₃Ph 9-30 1 CH₃ H/H

p-ClPh 9-31 1 CH₃ H/H

p-ClPh 9-32 1 CH₃ CH₃/CH₃ CH₂CH₃/CH₂CH₃ p-ClPh 9-33 1 CH₃ H/H

p-OCH₃ 9-34 1 CH₃ CH₃/CH₃ CH₂CH₃/CH₂CH₃ 2,4-diClPh 9-35 1 CH₃ CH₃/CH₃CH₃/CH₃ 2,4-diClPh 9-36 1 CH₃ H/H

p-ClPh 9-37 4 CH₃ CH₃/CH₃ CH₂CH₃/CH₂CH₃ p-ClPh 9-38 4 CH₃ CH₃/CH₃

p-ClPh 9-39 1 CH₃ CH₃/CH₃

2,4-diClPh 9-40 1 CH₃ CH₃/CH₃ H/CH₂CH₃ p-ClPh 9-41 1 CH₃ H/H4-[bis(4-fluorophenyl)- o-ClPh methylene]-piperidin-1-yl 9-42 1 CH₃ H/H1,2,3,4-tetrahydro-6,7-dimethoxy- p-OCH₃Ph isoquinolin-2-yl

They are described as follows:

No. M.P. (° C.) Formula Calc'd/Found (C, H, N) Rxn Solv 9-1 114-116C₁₉H₂₁ClN₂O₂ 66.18, 6.14, 8.12 neat 66.45, 6.12, 7.9 9-2 96-98C₂₀H₂₃ClN₂O₃ 64.08, 6.18, 7.47 i-PrOH 64.14, 6.16, 7.38 9-3 102-104C₂₁H₂₅ClN₂O₂ 61.62, 6.40, 6.84 EtOH 61.58, 6.67, 6.64 9-4 182-185C₁₈H₂₁ClN₂O₂-HCl 58.54, 6.01, 7.51 EtOH 58.57, 6.00, 7.66 9-5 115-117C₂₀H₂₃ClN₂O₂ 66.94, 6.46, 7.81 i-PrOH 67.10, 6.40, 7.76 9-6 195-197C₁₉H₁₈ClN₃O₂ 64.14, 5.10, 11.81 i-PrOH 64.02, 4.99, 11.75 9-7 210-213C₂₆H₂₉ClN₂O₄-HCl 61.78, 5.98, 5.54 i-PrOH 61.70, 5.92, 5.48 9-8 131-135C₁₈H₁₉ClN₂O₃ 62.41, 5.53, 8.09 i-PrOH 62.44, 5.91, 8.05 9-9 155-156C₂₄H₂₅ClN₂O₂C₂H₂O₂** 62.59, 5.45, 5.54 i-PrOH 62.56, 5.62, 5.61 9-10169-171 C₁₉H₂₁ClN₂O₂C₄H₄O₄* 59.94, 5.47, 6.08 i-PrOH 59.68, 5.40, 5.989-11 195-198 C₂₀H₂₃ClN₂O₂HCl 0.25H₂O 60.08, 6.18, 7.01, i-PrOH H₂O 1.1360.02, 6.16, 7.01, H₂O 1.29 9-12 113-116 C₁₈H₁₉ClN₂O₂-HCl 58.87, 5.49,7.63 i-PrOH 59.02, 5.53, 7.58 9-13 258-260 C₂₀H₂₃ClN₂O₃-HCl 58.40, 5.88,6.81 i-PrOH 58.17, 5.85, 6.76 9-14 248 (d) C₂₄H₂₇N₂O₂-HCl-0.25H₂O 63.79,6.36, 6.20 i-PrOH 63.79, 6.31, 6.10, H₂O 0.25 9-15 87-88C₁₉H₂₁ClN₂O₃0.8C₄H₄O₄-2/3H₂O* 57.93, 5.28, 5.87 i-PrOH 57.46, 5.54,5.83, KF 4.43 9-16 211-213 C₂₁H₂₅ClN₂O₂-HCl 0.25H₂O 60.95, 6.45, 6.77i-PrOH 61.13, 6.51, 6.90 9-17 136-138 C₁₈H₁₇N₃O₃ 66.86, 5.30, 13.00i-PrOH 66.90, 5.31, 12.87 9-18 190-192 C₂₀H₂₄N₂O₃-HCl 63.74, 6.69, 7.43i-PrOH 63.55, 6.66, 7.34 9-19 125-127 C₁₈H₁₉ClN₂O₃ 62.34, 5.52, 8.08i-PrOH 62.57, 5.49, 8.04 9-20 141-143 C₁₈H₁₉N₃O₅ 60.50; 5.36, 11.76i-PrOH 60.59; 5.24, 11.67 9-21 225-227 C₁₉H₂₁N₃O₄-HCl 58.24, 5.66, 10.72i-PrOH 58.20, 5.79, 10.52 9-22 105-107 C₂₁H₂₅ClN₂O₂ 67.64, 6.76, 7.51i-PrOH 67.67, 6.74, 7.58 9-23 190-193 C₁₉H₂₁ClN₂O₂-HCl 59.85, 5.82, 7.35i-PrOH 59.92, 5.85, 7.41 9-24 243-245 C₁₈H₁₉ClN₂O₂—HClO₄ 50.13, 4.67,6.50 neat 50.21, 4.65, 6.50 9-25 198-200 C₁₈H₁₉ClN₂O₃-HCl 56.41, 5.27,7.31 i-PrOH 56.49, 5.24, 7.30 9-26 242-245 C₁₇H₁₇ClN₂O₂-HClO₄ 48.94,4.35, 6.71 i-PrOH 49.01, 4.38, 6.72 9-27 173-176 C₁₇H₁₇ClN₂O₃ 61.35,5.10, 8.42 i-PrOH 61.21, 5.13, 8.59 9-28 259-262 C₁₆H₁₇ClN₂O₂-HCl0.25H₂O 55.58, 5.39, 8.10 i-PrOH 55.93, 5.56, 8.07 9-29 165-168C₁₉H₂₄N₂O₃-HCl 62.55, 6.91, 7.68 i-PrOH 62.25, 6.93, 7.60 9-30 118-122C₁₈H₁₉ClN₂O₂ 65.35, 5.79, 847 neat 65.29, 5.85 9-31 173-175C₁₇H₁₇ClN₂O₂—C₂H₂O₄ 56.10, 4.71, 6.89 i-PrOH 55.71, 4.68, 6.82 9-32176-178 C₂₀H₂₅ClN₂O₂ 1.5C₄H₄O₄-0.1EtOH* 58.31, 5.91, 5.18 i-PrOH 57.96,5.85, 5.18 9-33 114-115 C₁₉H₂₂N₂O₃-HCl-0.6H₂O 61.07, 6.53, 7.50 i-PrOH60.74, 6.83, 7.29 9-34 165-168 C₂₀H₂₄Cl₂N₂O₂C₄H₄O₄* 56.37, 5.52, 5.48i-PrOH 56.34, 5.70, 5.43 9-35 119 C₁₈H₂₀Cl₂N₂O-HCl 0.75H₂O 51.75, 5.48,6.55, toluene H₂O 3.71 51.77, 5.44, 6.71, H₂O 3.31 9-36 218-219C₁₈H₁₆ClN₃O₂ 63.25, 4.72, 12.29 i-PrOH 63.20, 4.82, 12.27 9-37 71-73C₂₃H₃₁ClN₂O₂ 68.56, 7.75, 6.95 neat 68.52, 7.86, 6.90 9-38 177-178C₂₄H₃₁ClN₂O₂—C₄H₄O₄* 63.33, 6.64, 5.28 i-PrOH 63.25, 6.67, 5.23 9-39177-179 C₂₀H₂₂Cl₂N₂O—HCl 0.4H₂O 55.22, 5.87, 6.05, i-PrOH H₂O 1.5555.06, 5.39, 6.05, H₂O 1.56 9-40 259-262 C₁₆H₁₇ClN₂O₂—HCl 0.25H₂O 55.58,5.39, 8.10, MeOH/ H₂O 1.30 EtOH 55.93, 5.56, 8.07, H₂O 1.39 9-41 189-191C₃₂H₂₇ClF₂N₂O₂—HCl 0.16H₂O 65.77, 4.88, 4.79 i-PrOH/ 65.85, 4.89, 4.80DIPEA* 9-42 248-251 C₂₆H₂₈N₂O₅—HCl 0.4H₂O-0.25EtOH 63.15, 6.27, 5.56i-PrOH/ 63.27, 6.52, 5.51 DIPEA *DIPEA: diisopropylethylamine

EXAMPLE 10

2-Chloro-1-(1-Methyl-1H-pyrrol-2-yl)-ethanone

A solution of 15 g (0.186 mole) N-methylpyrrole and 19.2 mL (0.186 mole)chloroacetyl chloride in 600 mL dry THF was heated under refluxovernight with a nitrogen stream bubbling through the reaction mixture.After cooling, the organics were washed with water, 1N NaOH, water,brine and dried (MgSO₄). Evaporation of the solvent gave 31.2 g of agreen solid: mp (decomp.) 280° C.; NMR 300 MHz (CDCl₃) d 7.05 (d, 1H);6.95 (s, 1H); 6.2 (m, 1H); 4.5 (s, 2H); 3.9 (s, 3H).

EXAMPLE 11

2-Chloro-1-[4-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-2-yl]-ethanone

solution of 30 g (0.19 mole) of2-chloro-1-(1-methyl-1H-pyrrol-2-yl)-ethanone (10) in 180 mL1,2-dichloroethane (DCE) under an argon atmosphere was cooled in an icebath and 60 g AlCl₃ (0.45 mole) was added in portions. After stirringfor 10 minutes, a solution of 24 mL (0.19 mole) 4-chlorobenzoyl chloridein 110 mL DCE was added dropwise. The ice bath was removed and thereaction was stirred at room temperature overnight. The reaction waspoured into 1N HCl/ice and the aqueous layer was extracted three timeswith methylene chloride. The organics solutions were combined, washedwith water, 1N NaOH, water, brine, and dried (MgSO₄). Evaporation of thesolvent in vacuo gave a solid which was recrystallized from ethylacetate/methylcyclohexane to give 27.67 g of a solid: mp 130-132° C.;NMR 300 MHz (CDCl₃) d 7.8 (m, 2H); 7.6-7.4 (m, 4H); 4.5 (s, 2H); 4.0 (s,3H). Anal Calcd for C₁₄H₁₁Cl₂NO₂: C, 56.78; H, 3.74; N, 4.73. Found: C,56.72; H, 3.76; N, 4.73.

EXAMPLE 12

1-[4-(4-Chlorobenzoyl)-1-methyl-1H-pyrrol-2-yl]-2-(1-piperidinyl)-ethanone

A solution of 4 g (0.013 mole) of2-chloro-1-[4-(4-chlorobenzoyl)-1-methyl-1H -pyrrol-2-yl]-ethanone (11)and 4.08 mL (0.039 mole) of piperidine in 60 mL 2-PrOH was heated underreflux for 1 h. The solvent was evaporated in vacuo and the residue wastaken up in diethyl ether/THF, washed with water, brine, and dried(MgSO₄). Evaporation of the solvent gave a tan solid which wasrecrystallized from 2-PrOH to give 3.65 g of product: mp 129-130° C.;mass spectrum (Cl—CH₄) m/z=345 (M+1); NMR 300 MHz (CDCl₃) d 7.8 (m, 2H);7.6 (s, 1H); 7.45 (d, 2H); 7.35 (s, 1H); 4.0 (s, 3H); 3.6 (s, 2H); 2.5(br s, 4H); 1.6 (m, 4H); 1.4 (m, 2H). Anal Calcd for C₁₉H₂₁Cl₂N₂O₂: C,66.18; H, 6.14; N, 8.12. Found: C, 66.25; H, 6.16; N, 8.08.

EXAMPLE 13

By the procedure of example 12 and employing the appropriate amine inplace of piperidine the following products were prepared:

1-[4-(4-Chlorobenzoyl)-1-methyl-1H-2pyrrol-2-yl]-2-(1-morpholino)-ethanoneHydrochloride (13-1)

mp 264-267° C. Anal Calcd for C₁₈H₁₉ClN₂O₃-HCl: C, 56.41; H, 5.26; N,7.31. Found: C, 56.14; H, 5.50; N, 7.17.

1-[4-(4-Chlorobenzoyl)-1-methyl-1H-pyrrol-2-yl]-2-(1-pyrrolidinyl)-ethanoneHydrochloride (13-2)

mp 265-267° C. Anal Calcd for C₁₈H₁₉ClN₂O₂-HCl: C, 58.87; H, 5.49; N,7.63. Found: C, 58.83; H, 5.66; N, 7.54.

EXAMPLE 14

4-(Pyrrolidin-1-yl)-1-[5-(4-pyrrolidin-1-ylbenzoyl)-1-methyl-1H-pyrrol-3-yl]-butanoneHydrochloride

A 10 g (0.03 mole) sample of4-chloro-1-[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-butanone wasadded to 18 mL (0.216 mole) of pyrrolidine and the mixture heated underreflux for 4 h. The solvent was evaporated in vacuo and the residuetriturated with Et₂O. The mixture was filtered and the filtrate treatedwith ethereal HCl to give the salt. Recrystallization from CH₃CN gave1.18 g (9% yield) of a yellow solid: mp 203-206° C. ¹H NMR (Me₂SO-d₆) d1.85-2.05 (m, 10H); 2.87-3.05 (m, 4H); 3.1-3.15 (m, 2H); 3.3-3.4 (m,4H); 3.45-3.55 (broad s, 2H); 3.9 (s, 3H); 6.62 (d, 2H); 6.96 (s,1H);7.72 (d, 2H); 7.92 (s, 1H). Anal Calcd for C₂₄H_(31N3)O₂-HCl-0.4CH₃CN:C, 66.73; H, 7.50; N, 10.67. Found: C, 66.34; H, 7.43; N, 10,33.

EXAMPLE 15

2-[(Bis-formyl)amino]-1-[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-ethanone

A solution of 10 g (0.034 mole) of2-chloro-1-[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-ethanone and3.8 g (0.041 mole) sodium diformylamide in 80 mL acetonitrile was heatedunder reflux overnight under argon. An additional 2.0 g portion ofsodium diformylamide was added and reflux was continued for 1.5 hrs.After evaporation of the solvent in vacuo the residue was passed througha flash column (silica gel, 3:1 hexane:acetone the 2:1 hexane:acetone)to give 6.18 g of a solid. mp 279-282° C. 260° C. decomp. mass spectrum(Cl—CH₄) m/z=333 (M+1). NMR 300 MHz (CDCl₃) d 9.0 (s, 2H); 7.8 (d, 2H);7.55 (s, 1H); 7.45 (d, 2H); 7.1 (s, 1H); 4.85 (s, 2H); 4.1 (s, 3H).

EXAMPLE 16

2-Amino-1-[5-(4-Chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-ethanoneHydrochloride

6.18 g (0.0186 mole)2-[(Bis-formyl)amino]-1-[5-(4-chlorobenzoyl)-1-methyl-1H-pyrrol-3-yl]-ethanone was stirred 3 days in 5% HCl/EtOH. A 0.5 mLportion of conc. HCL was added and the reaction stirred for two moredays. The solid was collected by filtration. The solid was stirred inrefluxing methanol and the undissolved solid collected by filtration anddiscarded. The filtrate was cooled to room temperature and diethyl etherwas added. The solid was collected. It was twice treated with boilingmethanol to give pure product: mp 290° C. (decomp.); mass spectrum(CH₄-Cl) m/z=277 (M+1); NMR (Me₂SO-d₆) d 8.2 (br s, 4H); 7.85 (d, 2H);7.6 (d, 2H); 7.2 (s, 1H); 4.3 (s, 2H); 4.0 (s 3H). Anal Calcd forC₁₄H₁₃ClN₂O₂-HCl: C, 53.69; H, 4.51; N, 8.94. Found: C, 53.91; H, 4.4.1;N, 8.76.

What is claimed is:
 1. A method for the treatment of neuropathic paincomprising the step of administering to a mammal suffering from suchcondition an effective amount, in a pharmaceutically acceptable carrier,of an active compound of the formula:

wherein, A is

 n is an integer from 1 to 5; R¹ is selected from the group consistingof H and C₁₋₄alkyl; R² and R³ are selected from the group consisting ofH and C₁₋₄alkyl; R⁴ and R⁵ are independently selected from the groupconsisting of H, C₁₋₄alkyl, phenyl C₁₋₄ alkyl and substituted phenylC₁₋₄ alkyl where the substituent is on phenyl and selected from thegroup consisting of methyl and methoxy, or in the alternative, are fusedand together with said nitrogen form a heterocyclic ring selected fromthe group consisting of 4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl,1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-2-yl,

wherein Y is S or O, x is 3 to 7 and R⁷ is selected from the groupconsisting of methyl and hydroxymethyl; and R⁶ is selected from thegroup consisting of halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, hydroxy, nitro,amino, C₁₋₄ acylamino, cyano, trihaloC₁₋₄alkyl, C₁₋₄alkylsulfonyl,C₁₋₄alkylsulfinyl, and C₁₋₄ acyl, including pharmaceutically acceptableacid addition salts thereof.
 2. The method of claim 1 wherein R¹ of saidformula of said active compound is selected from the group consisting ofhydrogen, methyl, ethyl, n-propyl and i-propyl.
 3. The method of claim 1wherein R² and R³ of said formula of said active compound areindependently selected from the group consisting of hydrogen, methyl,ethyl, n-propyl and i-propyl.
 4. The method of claim 1 wherein R⁴ and R⁵of said formula of said active compound, where independently selected,are selected from the group consisting of hydrogen, methyl, ethyl,n-propyl, i-propyl, benzyl and 2-phenyleth-1-yl where the phenyl ringmay be mono- or di-substituted with a substituent selected from thegroup of methyl and methoxy.
 5. The method of claim 1 wherein R⁴ and R⁵of said formula of said active compound, where fused and depictedtogether with nitrogen, are selected from the group consisting of4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl,1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-2-yl,


6. The method of claim 1 wherein R⁶ of said formula of said activecompound is selected from the group consisting of bromine, chlorine,methyl, ethyl, methoxy, ethoxy, hydroxy, nitro, amino, formylamino,acetylamino, cyano, perfluoromethyl, 3,3,3-trifluoropropyl,methylsulfonyl, methylsulfinyl, formyl and acetyl.
 7. The method ofclaim 1 wherein said pharmaceutically acceptable salt of said formula ofsaid active compound is selected from the group consisting ofhydrochloride, sulfate, phosphate, methane sulfonate, fumarate, maleate,citrate and lactate.
 8. The method of claim 1 wherein said formula ofsaid active compound has the formula:

wherein n, R¹, R², R³, R⁴, R⁵ and Ar are selected in concert from thegroup consisting of: n R¹ R²/R³ R⁴/R⁵ Ar 1 CH₃ H/H

p-ClPh; 1 CH₃ CH₃/CH₃

p-ClPh; 1 CH₃ CH₃/CH₃

p-ClPh; 1 CH₃ H/H CH₂CH₃/CH₂CH₃ p-ClPh; 1 CH₃ CH₃/CH₃

p-ClPh; 1 CH₃ CH₃/CH₃

p-ClPh; 1 CH₃ CH₃/CH₃

p-ClPh; 1 CH₃ H/H

p-ClPh; 1 CH₃ CH₃/CH₃

p-ClPh; 1 CH₃ H/H

o-ClPh; 1 CH₃ H/H

p-ClPh; 1 CH₃ H/H

o-ClPh; 1 CH₃ H/H

p-ClPh; 1 CH₃ H/H 1-Adamantyl o-ClPh; 1 CH₃ H/H

p-ClPh; 1 CH₃ H/H

P-ClPh; 1 CH₃ H/H

p-OCH₃Ph; 1 CH₃ H/H

p-OCH₃Ph; 1 CH₃ H/H

o-ClPh; 1 CH₃ H/H

p-NO₂Ph; 1 CH₃ H/H

p-NO₂Ph; 1 CH₃ H/H

p-ClPh; 1 CH₃ H/H

m-ClPh; 1 CH₃ H/H

m-ClPh; 1 CH₃ H/H

m-ClPh; 1 H H/H

p-ClPh; 1 H H/H

p-ClPh; 1 CH₃ H/H H/CH₂CH₃ p-ClPh; 1 CH₃ H/H CH₂CH₃/CH₂CH₃ p-OCH₃Ph; 1CH₃ H/H

p-ClPh; 1 CH₃ H/H

p-ClPh; 1 CH₃ CH₃/CH₃ CH₂CH₃/CH₂CH₃ p-ClPh; 1 CH₃ H/H

p-OCH₃; 1 CH₃ CH₃/CH₃ CH₂CH₃/CH₂CH₃ 2,4-diClPh; 1 CH₃ CH₃/CH₃ CH₃/CH₃2,4-diClPh; 1 CH₃ H/H

p-ClPh; 4 CH₃ CH₃/CH₃ CH₂CH₃/CH₂CH₃ p-ClPh; 4 CH₃ CH₃/CH₃

p-ClPh; 1 CH₃ CH₃/CH₃

2,4-diClPh; 1 CH₃ CH₃/CH₃ H/CH₂CH₃ p-ClPh; 1 CH₃ H/H4-[bis(4-fluorophenyl)- o-ClPh; methylene]-piperidin-1-yl 1 CH₃ H/H1,2,3,4-tetrahydro-6,7- p-OCH₃Ph; dimethoxy-isoquinolin-2-yl 1 CH₃CH₃/CH₃

2,4-diClPh; 3 CH₃ H/H

p-pyrrolidin-1-yl-Ph; and 1 CH₃ H/H H/H p-ClPh.


9. The method of claim 1 wherein said active compound is selected fromthe group consisting of: